Differential expansion of T central memory precursor and effector subsets is regulated by division speed

Abstract

While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8 + T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that slower cycling central memory precursors, characterized by an elongated G1 phase, segregate early from the bulk of rapidly dividing effector subsets, and further slow-down their cell cycle upon premature removal of antigenic stimuli. In contrast, curtailed availability of inflammatory stimuli selectively restrains effector T cell proliferation due to reduced receptivity for interleukin-2. In line with these findings, persistence of antigenic but not inflammatory stimuli throughout clonal expansion critically determines the later size of the memory compartment.

Precursor abundance influences divergent antigen specific CD8+ T cell responses after Yersinia pseudotuberculosis foodborne infection

“…The copyright holder for this preprint (which this version posted May 11, 2021. ; https://doi.org/10.1101/2021.05.10.443536 doi: bioRxiv preprint random combinations of both YopE and OVA-specific T cell clones, the values of this ratio became variable, but in average, the ratio increased overtime. Division speed of antigen-specific CD8 + T cells has been shown to impact central memory formation in that central memory precursors divide slower (16). This is consistent with our observation that higher percentage of OVA-specific cells are MPECs at 14 and 30 dpi in both livers and spleens (Fig.…”

SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection

“…Cytokine polyfunctionality is associated with increased protection from infection for multiple viruses (Lichterfeld et al, 2004, Sridhar et al, 2013), and associated with cellular division and terminal differentiation (Denton et al, 2011). Whilst differentiation of T cell memory phenotypes occurs early during infection and can reflect the extent of inflammation (Kretschmer et al, 2020), impacting recall capacity long-term (Kinjyo et al, 2015) to infected tissues (Weninger et al, 2001).…”

CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory

“…Lymphocyte differentiation is tightly regulated during cell proliferation (30)(31)(32), though it is unknown whether acute manipulation of cell cycle machinery has a directional influence on cell fate. To determine if the emergence of T cell memory observed in CDK4/6i-treated tumors was due to the direct inhibition of CDK4/6 within these cells, we exposed activated primary mouse CD8+ T cells to CDK4/6i in vitro and monitored Tcm acquisition and division number.…”